GLDC维持转移肿瘤干细胞特性在卵巢癌转移进程中的作用和分子机制研究

Ovarian cancer is the highest lethal gynecological malignance, over 90% of mortality is attributable to metastasis. Thus, it is particularly urgent to explore new metastatic mechanisms and to find new and effective regulation of target. Study on the ovarian cancer metastasis were limited to the effects of microenvironment on the metastasis, but it has not been reported the correlation between the metastatic cancer stem cells and ovarian cancer metastasis. GLDC was a peritoneal-specific metastasis gene of ovarian cancer that was screened in peritoneal-specific metastasis model by our laboratory. In the previous research, we found that GLDC was involved in the regulation of the metastatic potential and characteristics of stem cells in ovarian cancer. This project aims to use the in situ model of ovarian cancer and in vivo imaging to observe the role of GLDC in the metastasis progression of ovarian cancer and to explore the molecular mechanism of the metastasis regulation by metastatic cancer stem cell. A large clinical sample detects the correlation between the expression of GLDC and clinical prognosis of ovarian cancer. Completing this project not only has important theoretical significance to elucidate the regulation mechanisms of GLDC in ovarian cancer metastasis, but also reveals new ovarian recurrence and metastasis mechanisms, and provides new molecular targets and theoretical basis for suppressing or even eliminating ovarian cancer metastasis.

卵巢癌是死亡率最高的妇科恶性肿瘤，死亡原因中超过90%为复发转移。因此，探索新的卵巢癌转移机制，寻找卵巢癌新的有效调控靶点尤为迫切。既往关于卵巢癌转移的研究多局限于转移微环境对转移的影响，而关于转移肿瘤干细胞与卵巢癌转移相关性的研究尚无报道。GLDC是本实验室利用人卵巢癌腹腔特异性转移的原位模型筛选获得的卵巢癌腹腔特异性转移相关基因。前期研究中，我们发现GLDC参与调控卵巢癌转移及卵巢癌干细胞特性。本项目拟运用卵巢癌原位成瘤模型和小动物活体成像观察GLDC在卵巢癌转移中作用，证实其通过维持转移肿瘤干细胞特性参与卵巢癌转移进程，并深入探讨其分子机制。同时利用临床大样本检测卵巢癌中GLDC的表达与临床预后的相关性。完成本项目不仅对阐明GLDC调控卵巢癌转移机制具有重要理论意义，而且对全面揭示卵巢癌复发转移机制，为卵巢癌转移病灶得到抑制甚至完全清除提供新的分子靶点和理论依据。

卵巢癌是妇科三大恶性肿瘤之一。难治性及死亡率高的根本原因在于其难以早期诊断。卵巢癌转移易发生与盆腹腔，尤其是大网膜部位。然而目前卵巢癌转移的相关机制尚不清晰。前期我们利用卵巢癌小鼠原位模型筛选获得高低转移潜能的细胞系，基因芯片数据分析筛选出一系列转移相关基因。我们研究发现GLDC在卵巢癌转移中起着至关重要的作用。高转移细胞中下调GLDC表达后，卵巢癌细胞转移潜能明显下降。高表达GLDC后卵巢癌细胞干细胞成球能力增加，干细胞相关转录因子包括LGR5明显增高，分离临床标本中的肿瘤细胞进行干细胞球培养发现，干细胞球中GLDC表达明显增高。下调LGR5后逆转高表达GLDC引起的高转移潜能。分析临床样本发现GLDC表达与卵巢癌临床分期，复发转移及临床预后明显相关。因此GLDC可以作为卵巢癌治疗的新靶点。